Issue 69, 2018

Multiple 3D-QSAR modeling, e-pharmacophore, molecular docking, and in vitro study to explore novel AChE inhibitors

Abstract

Ligand-based and energy-optimized structure-based approaches were considered to obtain excellent candidates as AChE inhibitors. The known AChE inhibitors were utilized to develop a pharmacophore hypothesis, HPRRR and X-ray crystallographic structures of AChE were used to produce three e-pharmacophore hypotheses viz. AHHRR, AHRR, and DHRR. Based on in silico approaches, we came across eight structurally diverse hits as non-competitive AChE inhibitors with good ADME properties. The best four hits, ZINC20592007, ZINC05354646, ZINC20649934, and ZINC39154782 were non-toxic, neuroprotective, and were selective AChE inhibitors (IC50 values 482 ± 1.88 nM, 580 ± 1.63 nM, 854 ± 2.65 nM, and 636 ± 1.79 nM respectively). The hits showed non-competitive inhibition of AChE at PAS site with attractive Ki values (0.21 ± 0.027 μM, 0.27 ± 0.064 μM, 0.3 ± 0.018 μM, and 0.28 ± 0.032 μM for ZINC20592007, ZINC05354646, ZINC20649934, and ZINC39154782 respectively), and increased the cholinergic activity as well as inhibited Aβ aggregation.

Graphical abstract: Multiple 3D-QSAR modeling, e-pharmacophore, molecular docking, and in vitro study to explore novel AChE inhibitors

Supplementary files

Article information

Article type
Paper
Submitted
03 okt. 2018
Accepted
16 nóv. 2018
First published
26 nóv. 2018
This article is Open Access
Creative Commons BY-NC license

RSC Adv., 2018,8, 39477-39495

Multiple 3D-QSAR modeling, e-pharmacophore, molecular docking, and in vitro study to explore novel AChE inhibitors

S. Jana, A. Ganeshpurkar and S. K. Singh, RSC Adv., 2018, 8, 39477 DOI: 10.1039/C8RA08198K

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